Discovery and characterisation of the novel, pathological GNB3 mutation (D153del/ Gβ_3D), in the retinopathy globe enlarged (rge) chicken

The common human GNB3 825C&gt;T variant, which is present in 50% of the world’s chromosomes, has previously been shown to predispose individuals to hypertension, cardiac and neural disorders. This variant causes the production of a stable and gain of function protein Gβ_3S- This thesis describes the discovery of a novel D153del mutation that produces an unstable, loss of function, protein Gβ<sub style="background-color: rgb(255, 255, 255);">3D </sub>in the recessively inherited, retinopathy globe enlarged (rge) chickens. This thesis also demonstrates that the normal Gβ<sub style="background-color: rgb(255, 255, 255);">3 </sub>downstream phosphorylation signalling pathways are significantly altered in a tissue specific manner in rge chicken organs and in a human GNB3 825TT lymphoblast cell line. In rge tissues expressing Gβ<sub style="background-color: rgb(255, 255, 255);">3D </sub>protein, the cAMP induced GRK2 phosphorylation activity is significantly altered. Moreover MAPK1 (ERK2) phosphorylation is significantly decreased compared to normal tissues. In contrast human 825TT cell lines expressing the Gβ<sub style="background-color: rgb(255, 255, 255);">3S </sub>protein, showed enhanced cAMP induced GRK2 and MAPK (ERK1 and ERK2) phosphorylation activity. These results confirm previous findings of 825C&gt;T Gβ<sub style="background-color: rgb(255, 255, 255);">3 </sub>studies, that Gβ<sub style="background-color: rgb(255, 255, 255);">3S </sub>is indeed a hyper-activating structural variant, in contrast to the D153del Gp3D is a classical recessively inherited non-functional mutation.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Abertay Dundee

Year dc:date.issued

2008

Author dc:creator

• Tummala, Hemanth

Advisor dc:contributor.advisor

• Lester, Douglas

• G-protein
• Genetic polymorphism
• GTPase
• Pharmacogenetics
• Splice variant
• Signal transduction
• Neurological disorders
• Hypertension,
• Cardiac disease

Language dc:language

eng

Identifier

oai:rke.abertay.ac.uk:studenttheses/baf432d1-5f39-43bd-9e47-abc3813985ad

OAI identifier oai:identifier

oai:rke.abertay.ac.uk:studenttheses/baf432d1-5f39-43bd-9e47-abc3813985ad